Marcelo Cypel MD MSc

Canada Research Chair in Lung Transplantation

Surgical Director, ECLS program UHN

Assistant Professor of Surgery

Division of Thoracic Surgery

University of Toronto

Managing an Organ - New Therapies

DISCLOSURE

• Vitrolife, XVIVO Perfusion – Research support

and clinical trial

• Co-founder and Medical Officer Perfusix Canada

and United States

• Co-founder XOR Toronto Labs

First Successful Lung Transplantation in the World Toronto General Hospital1983

First Lung Tx

First Double Lung Tx

5

Indications(TGH) N=1500

Eisenmenger's

3%

Cystic Fibrosis

22%

ILD/IPF

31%

Other

3%

Re-Tx

3%

COPD/

Emphysema

33%

PAH

5%BAC

1%

Major Obstacle for Lung Transplantation Success

•Absence of sufficient organs to meet the growing demand!

•Up to 30% patients die on wait lists

• Larger number of patients are not even listed

Low Utilization Rates

www.unos.org.2011

BDD=17% DCD=2%

Munshi L, Keshavjee S, Cypel M. The Lancet RM Volume 1, Issue 4, Pages 318 - 328, June 2013

Clinical Problem - PGD

Reduction of cell metabolism by 95%

Normothermic Preservation

• Time to accurately assess, diagnose (improve utilization)

• Option to treat, recover, repair (targeted)

• Opportunity to reassess confirm results of treatment

Lindbergh, Science, 1935

Couves, CM

TORONTO EX VIVO LUNG PERFUSION (EVLP) SYSTEM

Perfusion : 40% CO, LAP 5mmHg, PAP 10-12mmHg

Ventilation: 7cc/kg, 7BPM, PEEP 5, FiO2 = 21%

Cypel et al. J Heart Lung Transplant 2008; 27(12):1319-25.

Toronto Sky Dome Toronto XVIVOTM System

DEVELOPMENT OF A STABLE AND RELIABLE EX VIVO LUNG PERFUSION TECHNIQUE

Cypel/Keshavjee. Technique for Prolonged Normothermic Ex Vivo Lung

Perfusion. J Heart Lung Transplant 2008;27(12):1319-25.

NORMOTHERMIC EX VIVO PERFUSION INTERRUPTS COLD ISCHEMIC INJURY (24h)

CSP EVLP

Cypel/Keshavjee. Normothermic ex vivo perfusion prevents lung injury compared to extended

cold preservation for transplantation. Am J Transplant. 2009 Oct;9(10):2262-9

VIDEO

22

NEJM, April 14th 2011, vol. 364, no. 15, pp. 1431-1440.

Study Logistics

Donor Lungs Referred for EVLP

Cold Ischemic Time 1 (transportation)

EVLP for 4-6h P/F>400mmHg, stable or improved PawP, PVR, Compliance, X-ray

Cold Ischemic Time 2

Transplantation

Bronchoscopy

Lung Xray

Stable or Improved Ex vivo Function

Early outcomes were similar in the 2 groups

NEJM, April 14th 2011

Cypel et al. Experience with the first 50 ex vivo lung perfusions in clinical

lung transplantation. JCTVS September 2012

Survival

0 365 730 1095 1460

0

20

40

60

80

100controls (n=253)

EVLP (n=50)

1 2 3 4

p=0.69

Years after LTx

Perc

en

t su

rviv

al

Cypel et al. Experience with the first 50 ex vivo lung perfusions in clinical

lung transplantation. JCTVS September 2012

Survival

0 365 730 1095 1460

0

20

40

60

80

100controls (n=253)

EVLP BDD (n=28)

EVLP DCD (n=22)

p=0.71

1 2 3 4

Years after LTx

Perc

en

t su

rviv

al

EVLP Experience in Toronto

Assessed

(n=105)

Transplants (n=84) Transplants (n=21)

Utilization Rate of EVLP Lungs

84/105 = 80%

0

20

40

60

80

100

120'0

8

'09

'10

'11

'12

'13

No

of

Tx /

yr

Year

EVLPLung Tx

Current State of EVLP

•> 300 cases done North America and Europe

•3 clinical trials (1 US and 2 Europe)

•XVIVO, Transmedics, Vivoline

Engineering Superior Organs

Ex vivo treatment opportunities Donor lung injuries

1- Pulmonary Edema

2- Brain death associated inflammation

3- Infection, Pneumonia

4- Aspiration

5- Pulmonary emboli

6- Ischemia-reperfusion injury

7- Immunologic preparation

Advantages of ex vivo treatment

• Increased time for interventions

• Avoid systemic side effects

• Treatment is specific to the organ

• Prolonged half-life of drugs in perfusate

• Absence of systemic inflammatory milieu

• Opportunity for post-treatment re-assessment

Resolution of pulmonary edema during EVLP

Donor P/F 230

1h EVLP

3h EVLP

Recipient P/F 420

Infection

•Large proportion of rejected human lungs

•EVLP is ideal

• Super high doses of antibiotics can be

administered without systemic effects

• Prolonged half-life.

•Start with treatment of early infections or lung contralateral to established pneumonia

•Prolonged perfusion (>12h) might be required

Repairing Human Lungs with Presumed Infection

• 6 lungs rejected for suspicion of infection

• 12h normothermic EVLP with high doses of antibiotics

0

100

200

300

400

500

600

1 3 6 9 12

Pneumonia - Mean Delta pO2 (FiO2 1)

40

Ex Vivo Treatment of Infection

0

20

40

60

80

100

120

0h 6h 12h

10

6 C

FU

/L

Ps Aeruginosa (n= 4)

0

20

40

60

80

100

120

0h 6h 12h

10

6 C

FU

/L

S Aureus (n= 3)

0

20

40

60

80

100

120

0h 6h 12h

10

6 C

FU

/L

St Maltophilia (n= 3)

0

20

40

60

80

100

0h 6h 12h

10

6 C

FU

/L

Trichosporon (n= 3)

0

1

2

3

4

5

6

0h 6h 12h

10

6 C

FU

/L

E Coli (n= 2)

0

20

40

60

80

100

120

0h 6h 12h

10

6 C

FU

/L

Enterobacter (n= 1)

control

control

Clinical Case:

Diagnosing and Treating a Specific Problem

41

Personalized Medicine for the Organ

Surgical Extraction of Large Clots of Varying Age in Donor Lung PA

EVLP Assessment confirms the in vivo findings

• On initiation of EVLP: abnormal PA pressures even with low flows

Persistent hemodynamic

impairment in the ex vivo organ

Apply similar diagnosis / treatment

as in vivo treatment of massive PE

ALTEPLASE 20 mg (reduced

clearance)

Significant improvement of Pulmonary Hemodynamics after treatment

treatment

Response monitoring

diagnosis

Alteplase

D-dimer and Evidence of Thrombolysis

11-fold

increase

Ex vivo treated lung

with massive PE

Pathology: Ex vivo lung biopsy, Quick Section pathologic Examination

No evidence of chronic

vascular abnormalities

Functional Repair of Human Donor Lungs by Ex Vivo IL-10 Gene Therapy

M Cypel, M Liu, M Rubacha, J C Yeung, S Hirayama, M Anraku, M Sato, J Medin, BL Davidson, M de Perrot, TK Waddell, A S Slutsky, S Keshavjee. Sci Trans. Med 1:4ra9; 2009.

PaO2/FiO2

-100

0

100

200

300 *

Ch

an

ge

fr

om

B

ase

lin

e(m

mH

g)

PVR

-600

-400

-200

0

200

400

600

*

(dynes.s

ec.c

m-5

)

EVLP/AdIL-10 EVLP

Delivery of IL-10 by EVLP Ad Gene Therapy to injured human donor lungs

resulted in improved lung function

Recovery of alveolar epithelial cell tight junctions (ZO-1) after AdhIL-10 gene therapy in Human Lungs.

Cypel/Keshavjee et al. Science Translational Medicine Oct 28, 2009.

The Future of Transplantation… The “Organ Repair Center”

Heart Lung

Kidney Liver

Exterior Rendering Spring Street Façade/Orange

Donor Management

Organ Procurement

Cold Preservation

Ex vivo Evaluation

Ex vivo Organ-Specific Injury Repair

Transplantation

Thank you!

marcelo.cypel@uhn.ca

www.dotscanada.ca